Project Summary Congenital Ichthyosis (CI) is a heterogeneous group of inherited dermatological diseases characterized by abnormal skin growth and keratinization that can lead to scaling and skin thickening. Individuals with moderate to severe CI can have life-long symptoms including accumulating scales, itchy and/or cracked skin that is painful and bleeds. The itching, fissuring, and abnormal skin barrier function associated with CI can cause further complications, including infection, and can significantly impact quality of life. Conservative prevalence estimates suggest there are around 130,000 individuals in the United States with CI, making this an Orphan Disorder. Currently there are no FDA-approved therapies for CI. Hydrants and lubricants can facilitate hydration but do not address the underlying disease abnormalities. Off-label use of oral retinoids can improve symptoms and has been used to treat certain types of CI. However, symptoms quickly recur when treatment is stopped. In addition, oral retinoids have serious side effects that preclude their long-term use. These include teratogenic risk, skin fragility, elevated blood concentrations of triglycerides and liver enzymes, and diffuse skeletal hyperostosis. Topical isotretinoin, which is approved outside of the US and used to treat severe acne, is a better candidate for long-term CI treatment as it has a shorter half-life and less teratogenic risk than other retinoids. However, topical isotretinoin formulations have poor delivery of the active article to the epidermis and dermis and require high concentrations of ethanol as a penetrant enhance, which can cause significant erythema when applied over large body surface areas. Similar to oral retinoids, topical isotretinoin is contraindicated for long- term use for CI. Development of a safe and effective therapeutic indicated for CI has been difficult, despite the well-recognized critical need for such a treatment. Patagonia is pioneering an innovative topical isotretinoin ointment for CI: PAT-001. This patent-pending formulation has no ethanol and has minimal systemic absorption. In addition, unlike current formulations, isotretinoin is selectively targeted to the epidermis and dermis. PAT-001 was granted Orphan Drug Designation in 2014, and Patagonia has completed pre-clinical GLP pharmacokinetics and toxicology studies, including 90- day repeat-dose dermal toxicity study in minipigs, sensitization study in guinea pigs, bovine corneal opacity and permeability study, and phototoxicity in rabbits. Patagonia has also completed a dermal range-finding study in minipigs, which was not required to be GLP-compliant. These studies indicated that therapeutic concentrations of PAT-001 selectively reached targeted tissues with minimal systemic absorption and had no evidence of new or unique toxicity. Based on these studies, we expect that PAT-001 will be as if not more effective than oral retinoids and other topical isotretinoin formulations with significantly fewer side effects. In this application, Patagonia will conduct a Phase 2 clinical trial (active IND 122,058, date of receipt 07/27/2016) in subjects aged 12 and older with Lamellar and Recessive X-linked Ichthyosis. Phase 2a is a multisite, randomized, double-blind, vehicle controlled, bilateral comparison study (8 weeks) with active only treatment follow-up (4 weeks). It will provide proof-of-concept safety and efficacy of PAT-001. The Aims of Phase 2a are to 1) Assess the safety and tolerability of PAT-001; 2) Assess the potential efficacy of PAT-001 compared to a vehicle; and 3) Conduct a pilot, exploratory PK study by determining plasma levels of isotretinoin and tretinoin from topically applied PAT-001 with comparison to background systemic retinoid levels pre-and post- treatment. Phase 2b will focus on dose-finding, safety, and efficacy; the protocol will be finalized based on the results of the Phase 2a and communication with the FDA at the end of Phase 2a meeting. This Phase 2 trial will facilitate advancement to Phase 3 and eventual NDA filing and agency approval of PAT-001 as the first and only FDA-approved therapy for CI.